In ventricular fibrillation, the leading cause of sudden cardiac death, electrical activity is marked by wavebreak and subsequent fragmentation of the wave of excitation. Recent work by several groups has focused on the mechanisms of this wavebreak. Anatomical complexity, enhanced by disease, is an important cause of wavebreak, but mathematical modelers have shown that dynamical factors are also critical in this process, independently of, and synergistically with, a disordered anatomical substrate. This paradigm shift towards dynamics is important therapeutically because dynamical factors, unlike anatomy, can be modified by drugs or gene therapy. This Project studies the dynamical mechanisms of fibrillation, in large-scale, realistic, computer models of ventricular conduction. These models, containing roughly 50 million variables, have been developed, and will be extended in this proposal to a level of physiological realism that will make them clinically relevant. Several mechanistic hypotheses will be tested in these "Virtual Heart" models (normal and diseased), the most important of which is that by intervening to improve wave stability, the induction of reentry and its breakdown into fibrillation can be prevented. Specific therapeutic approaches will be explored, including modifying Ca channel kinetics and its interaction with intracellular Ca cycling, especially in the phenomenon of "discordant alternans." The mechanisms of fibrillation, long elusive, can now be studied in silico in models like these, The detailed physiological knowledge is largely already in place; only the computational difficulty of such large-scale simulations remained as an obstacle. These problems have been tamed, through improved numerical methods and the use of supercomputers, so that these models can now be used to study the mechanisms of fibrillation, and potential therapies. The simulations will be performed interactively with theoretical and experimental approaches used in the other projects to define novel therapies for ventricular fibrillation and sudden cardiac death.